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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳進庭 | |
| dc.contributor.author | Po-Chun Peng | en |
| dc.contributor.author | 彭柏鈞 | zh_TW |
| dc.date.accessioned | 2021-05-14T17:46:35Z | - |
| dc.date.available | 2020-05-01 | |
| dc.date.available | 2021-05-14T17:46:35Z | - |
| dc.date.copyright | 2019-03-11 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-04-15 | |
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Seetharamu, N., et al., Phase II study of liposomal cisplatin (SPI-77) in platinum-sensitive recurrences of ovarian cancer. Anticancer Res, 2010. 30(2): p. 541-5. 157. Boulikas, T., et al., Systemic Lipoplatin infusion results in preferential tumor uptake in human studies. Anticancer Res, 2005. 25(4): p. 3031-9. 158. Stathopoulos, G.P., et al., Comparison of liposomal cisplatin versus cisplatin in non-squamous cell non-small-cell lung cancer. Cancer Chemother Pharmacol, 2011. 68(4): p. 945-50. 159. Wang, S., et al., Talaporfin sodium. Expert Opin Pharmacother, 2010. 11(1): p. 133-40. 160. Bandak, S., et al., Pharmacological studies of cisplatin encapsulated in long-circulating liposomes in mouse tumor models. Anticancer Drugs, 1999. 10(10): p. 911-20. 161. Veal, G.J., et al., A phase I study in paediatric patients to evaluate the safety and pharmacokinetics of SPI-77, a liposome encapsulated formulation of cisplatin. Br J Cancer, 2001. 84(8): p. 1029-35. 162. Devarajan, P., et al., Low renal toxicity of lipoplatin compared to cisplatin in animals. Anticancer Res, 2004. 24(4): p. 2193-200. 163. Allison, R.R., et al., Photosensitizers in clinical PDT. Photodiagnosis and Photodynamic Therapy, 2004. 1(1): p. 27-42. 164. Kato, H., et al., Phase II clinical study of photodynamic therapy using mono-L-aspartyl chlorin e6 and diode laser for early superficial squamous cell carcinoma of the lung. Lung Cancer, 2003. 42(1): p. 103-11. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/4758 | - |
| dc.description.abstract | 癌症為現代人類主要的死亡原因之一，目前常使用之治療方式中，將化療藥物包覆於微脂體之劑型，雖然能有效降低化療藥物副作用，但也減慢藥物釋放速度，使其療效大幅減弱。近年來我們發展利用光動力效應加速化療藥物由微脂體釋出之雙效微脂體，並發現其除了具有光動力治療與化學治療各自之效果外，還能造成微脂體中化療藥物釋放模式的改變，進而更加提高在活體動物實驗中對腫瘤之療效。為了驗證雙效微脂體的概念，並擴大其適用範圍，在本研究中，我們針對另一同因藥物釋放緩慢問題，而無法產生良好療效之微脂體藥物進行改良，建立結合光動力治療的雙效微脂體，並證實即使包覆不同化療藥物，依然能產生優良治療效力，對體積較大的腫瘤(500 mm3)也能發揮治癒功效。接著我們更進一步探討雙效微脂體的作用機制，發現其能藉由改善藥物釋放、增加藥物在腫瘤部位累積，以及促進藥物進入腫瘤細胞作用，來達到增進腫瘤治療能力的結果。最後我們更嘗試針對目前除手術外，並無較佳治療方式之人類惡性周邊神經鞘瘤進行治療探討。發現在小鼠腫瘤模式的實驗中，雙效微脂體能減少化療藥物的使用量，於治療後進行血液生化分析，顯示此治療方式具良好使用安全性，而且依然能展現完全清除腫瘤的功效，代表對人類惡性周邊神經鞘瘤也能達到應用。經由對雙效微脂體的了解，希望使其能有更進一步的發展，解決目前臨床腫瘤治療的需求。 | zh_TW |
| dc.description.abstract | Nowadays, cancer is one of the leading causes of mortality worldwide. Using liposome-encapsulated cancer chemotherapy significantly decreases side effects. However, entrapment of drug in liposomes may slow down drug release and attenuate anticancer efficacy. Previously, a dual-effect liposome triggered by photodynamic effect (PDT) was developed to improve the therapeutic efficacy of chemotherapeutic agent-loaded liposomes. Co-encapsulation of the photosensitizer and chemotherapeutic agent in liposome not only could display PDT and chemotherapy effect but also change the release profile of the chemotherapy drug from liposome, enhancing the anti-tumor effect in animal study. To verify the concept of dual-effect liposome and apply this strategy for cancer treatment, encapsulation of another liposomal chemotherapeutic agent in dual-effect liposome was performed. This newly dual-effect liposome could enhance anti-cancer efficacy even encapsulated with other chemotherapy drugs and revealed significant therapeutic effects even on large tumors (500 or 1000 mm3). Investigation of mechanism of dual-effect liposome showed that dual-effect liposome enhanced anti-cancer efficacy by (1) changing drug release, (2) increasing drug accumulation at the target tumor site, and (3) improving more chemotherapeutic medicine to enter the tumor cell. Treatment with dual-effect liposome significantly prevented tumor growth of malignant peripheral nerve sheath tumor (MPNST) which is a neurofibrosarcoma from neurofibromatosis type 1 and difficult to be cured. Analysis of blood chemistry showed it is safe to use dual-effect liposome for cancer treatment in murine model. In this study, we evaluated the feasibility of using dual-effect liposome to treat human cancer tumor xenografts in vivo, and expected to apply dual-effect liposome to clinical cancer therapy in the near future. | en |
| dc.description.provenance | Made available in DSpace on 2021-05-14T17:46:35Z (GMT). No. of bitstreams: 1 ntu-104-D99b22008-1.pdf: 5900572 bytes, checksum: 37094b7491e8b6665deaeee39faccc48 (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 目錄 摘要 7 Abstract 8 1.1癌症治療 9 1.2化學治療 9 1.3微脂體 10 1.3.1微脂體簡介 10 1.3.2微脂體在藥物傳輸的應用 12 1.3.3 Liposomal Doxorubicin 14 1.3.4 Liposomal Cisplatin 15 1.4光動力治療 16 1.4.1光化學作用機制 17 1.4.2光感物質 18 1.4.3 Liposomal Chlorin e6 19 1.5惡性周邊神經鞘瘤 20 1.5.1 Axl receptor tyrosine kinase 21 1.6研究動機與目的 22 第二章 材料與方法 24 2.1藥品與儀器 24 2.1.1 藥品 24 2.1.2 儀器 26 2.2 細胞株 26 2.2.1 細胞培養液 27 2.2.2 繼代培養方法 27 2.2.3 細胞解凍與冷凍方法 27 2.3 細胞計數 28 2.4 微脂體製備 28 2.5 微脂體內藥物定量 31 2.6 微脂體內脂質分析 32 2.7 PL-cDDP-Ce6保存穩定性分析 32 2.8 PL-cDDP-Ce6於血清中的穩定性分析 32 2.9微脂體藥物釋放分析 33 2.10 細胞存活率檢測 - MTT assay 33 2.11 活體動物實驗 34 2.11.1 動物與腫瘤模式 34 2.11.2 藥物於活體組織分佈 34 2.11.3 腫瘤組織細胞核內藥物分析 35 2.11.4 光動力治療 35 2.11.5 血漿中Soluble Axl (sAxl)檢測 36 2.11.6 血液生化分析及腫瘤組織切片 36 2.12 統計分析 37 第三章 結果 38 3.1雙效微脂體PL-cDDP-Ce6 38 3.1.1雙效微脂體PL-cDDP-Ce6基礎性質分析 38 3.1.2雙效微脂體PL-cDDP-Ce6之細胞毒殺效果 39 3.1.3雙效微脂體PL-cDDP-Ce6於C26小鼠腫瘤模式之治療 40 3.2雙效微脂體機制探討 44 3.2.1雙效微脂體PL-Dox-Ce6作用機制 44 3.2.2雙效微脂體PL-cDDP-Ce6作用機制 48 3.3雙效微脂體PL-cDDP-Ce6於人類惡性周邊神經鞘瘤之應用 51 3.3.1雙效微脂體PL-cDDP-Ce6對MPNST腫瘤細胞之毒殺效果 51 3.3.2雙效微脂體PL-cDDP-Ce6對MPNST小鼠腫瘤模式之治療 52 第四章 討論 56 4.1雙效微脂體的製備 56 4.1.1建構雙效微脂體PL-cDDP-Ce6 56 4.1.2脂質及光感物質對雙效微脂體製備的影響 56 4.2 PL-cDDP-Ce6用於腫瘤治療 59 4.3雙效微脂體應用機制探討 61 4.3.1光感物質對雙效微脂體治療成效的影響 65 4.4雙效微脂體尚待釐清之機制 65 4.5 PL-cDDP-Ce6於人類惡性周邊神經鞘瘤之應用 67 4.6 PL-cDDP-Ce6臨床應用未來展望 68 參考文獻 114 表目錄 表一、雙效微脂體PL-cDDP-Ce6特性分析。 72 表二、雙效微脂體PL-cDDP-Ce6保存於4℃之穩定性分析。 73 表三、靜脈注射雙效微脂體PL-cDDP-Ce6後，老鼠各器官藥物累積量。 74 表四、製作時加入 (A) 0.1、(B) 0.15、(C) 0.2 mg Ce6所製成之雙效微脂體PL-Dox-Ce6特性分析。 75 表五、靜脈注射雙效微脂體PL-Dox-Ce6後，於第2小時進行照光治療，小鼠之血液及組織藥物濃度對時間曲線下面積(AUC)。 76 表六、靜脈注射雙效微脂體PL-Dox-Ce6後，於第2小時進行照光治療，小鼠之藥物動力學參數。 77 表七、製作時不加入Ce6之PL-cDDP及加入 (A) 0.4、(B) 0.8、(C) 1.2、(D) 1.6、(E) 2.4 mg Ce6所製成之雙效微脂體PL-cDDP-Ce6特性分析。 78 表八、靜脈注射雙效微脂體PL-cDDP-Ce6後，於第2小時進行照光治療，小鼠之血液及組織藥物濃度對時間曲線下面積(AUC)。 79 表九、靜脈注射雙效微脂體PL-cDDP-Ce6後，於第2小時進行照光治療，小鼠之藥物動力學參數。 80 表十、以雙效微脂體PL-cDDP-Ce6對植有S462-TY腫瘤之小鼠進行治療後72小時之血液生化分析。 81 表十一、以雙效微脂體PL-cDDP-Ce6對植有S462-TY腫瘤之小鼠進行治療後72小時之全血細胞計數。 82 圖目錄 圖一、雙效微脂體PL-cDDP-Ce6對 (A) A375細胞，(B) A549細胞，(C) C26細胞之細胞毒殺效果。 84 圖二、靜脈注射雙效微脂體PL-cDDP-Ce6後，分別在第2或第12小時進行光動力治療之小鼠 (A)腫瘤大小，(B)生存率，(C)體重變化。 85 圖三、靜脈注射雙效微脂體PL-cDDP-Ce6後，於第2及第12小時進行光動力治療之小鼠 (A)腫瘤大小，(B)生存率，(C)體重變化。 86 圖四、腫瘤生長至300 mm3後，再以雙效微脂體PL-cDDP-Ce6進行治療之小鼠 (A)腫瘤大小，(B)生存率，(C)體重變化。 87 圖五、腫瘤生長至500 mm3後，再以雙效微脂體PL-cDDP-Ce6進行治療之小鼠腫瘤大小，生存率，體重變化。 88 圖六、雙效微脂體PL-Dox-Ce6照光後粒徑(A)及分散指數(B)變化。 89 圖七、包覆不同Ce6量之雙效微脂體PL-Dox-Ce6照光後Dox釋放情形。 90 圖八、靜脈注射雙效微脂體PL-Dox-Ce6後，於第2小時進行照光治療，小鼠之組織器官藥物累積量變化。 93 圖九、靜脈注射雙效微脂體PL-Dox-Ce6並進行照光治療後，小鼠腫瘤內Dox累積量。 94 圖十、雙效微脂體PL-cDDP-Ce6照光後粒徑(A)及分散指數(B)變化。 95 圖十一、包覆不同Ce6量之雙效微脂體PL-cDDP-Ce6於血清中的穩定性 (Ce6留存率)。 96 圖十二、包覆不同Ce6量之雙效微脂體PL-cDDP-Ce6於血清中的穩定性 (cDDP留存率)。 97 圖十三、包覆不同Ce6量之雙效微脂體PL-cDDP-Ce6照光後cDDP釋放情形。 98 圖十四、靜脈注射雙效微脂體PL-cDDP-Ce6後，於第2小時進行照光治療，小鼠之組織器官藥物累積量變化。 100 圖十五、雙效微脂體PL-cDDP-Ce6對MPNST cell lines (A) S462-TY細胞，(B) ST8814細胞，(C) T265細胞之細胞毒殺效果。 101 圖十六、(A) cDDP及(B) PL-cDDP對植有S462-TY腫瘤之小鼠進行治療，其腫瘤大小，生存率，體重變化。 102 圖十七、以不同Ce6劑量之雙效微脂體PL-cDDP-Ce6對植有S462-TY腫瘤之小鼠進行治療，小鼠 (A)腫瘤大小，(B)生存率，(C)體重變化。 103 圖十八、以雙效微脂體PL-cDDP-Ce6對植有S462-TY腫瘤之小鼠進行治療，小鼠 (A)腫瘤大小，(B)生存率，(C)體重，(D)血漿內sAxl變化。 104 圖十九、S462-TY腫瘤生長至1000 mm3後，再以雙效微脂體PL-cDDP-Ce6進行治療，小鼠 (A)腫瘤大小，(B)生存率，(C)體重變化。 105 圖二十、以雙效微脂體PL-cDDP-Ce6對植有S462-TY腫瘤之小鼠進行治療，治療後72小時之腫瘤切片。 106 附表一、 SPI-077、Lipoplatin及 PL-cDDP-Ce6比較。 107 附表二、 Temoporfin、Talaporfin及 Chlorin e6光動力治療比較。 108 附圖一、光動力作用模式。 109 附圖二、常見的磷脂質化學結構。 110 附圖三、(A) 雙效微脂體PL-Dox-Ce6的製備流程; (B)雙效微脂體PL-cDDP-Ce6的製備流程。 111 附圖四、以HPLC分析Pt(DDTC)2。 112 附圖五、雙效型微脂體PL-cDDP-Ce6示意圖。 113 | |
| dc.language.iso | zh-TW | |
| dc.subject | 人類惡性周邊神經鞘瘤 | zh_TW |
| dc.subject | 光動力治療 | zh_TW |
| dc.subject | 微脂體 | zh_TW |
| dc.subject | 藥物釋放 | zh_TW |
| dc.subject | 化學治療 | zh_TW |
| dc.subject | MPNST | en |
| dc.subject | Liposome | en |
| dc.subject | Chemotherapy | en |
| dc.subject | Photodynamic therapy | en |
| dc.subject | Drug release | en |
| dc.title | 光動力觸發微脂體化療藥物輸送系統之研究 | zh_TW |
| dc.title | Investigation of liposomal chemotherapy triggered by photodynamic treatment | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 黃慶璨,蔡翠敏,李銘仁,曾雲龍 | |
| dc.subject.keyword | 微脂體,化學治療,光動力治療,藥物釋放,人類惡性周邊神經鞘瘤, | zh_TW |
| dc.subject.keyword | Liposome,Chemotherapy,Photodynamic therapy,Drug release,MPNST, | en |
| dc.relation.page | 125 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2015-04-15 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科技學系 | zh_TW |
| 顯示於系所單位： | 生化科技學系 | |
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